1) Field of the Invention
The present invention generally relates to compounds having pharmacological activity which are useful as pharmacological agents and, more particularly, as analgesic agents for the treatment of pain, to pharmaceutical compositions containing one or more of these compounds, and to methods of treatment employing these compounds. More particularly, the present invention concerns substituted dibenzoxazepine compounds, pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and methods of treating pain employing these compounds.
Analgesic compounds are agents which alleviate pain without causing a loss of consciousness and, thus, which are useful for treating pain and, often, for reducing inflammation.
The major classes of analgesic compounds include narcotic analgesics, or opiates, compounds which alleviate pain and induce sleep, and analgesic-antipyretic compounds, compounds which alleviate pain and reduce fever, such as salicylates.
Although the efficacy of opiates in relieving pain is well established, the associated addiction liability of opiates is a distinct disadvantage of these compounds.
While salicylate and salicylate-like agents (non-steroidal antiinflammatory agents or NSAIDS) are also efficacious in relieving pain, they often exhibit undesirable side effects, such as gastrointestinal irritation, as with aspirin, allergic response, as with aspirin, and/or liver toxicity with extended use, as with acetaminophen.
The compounds of the present invention are neither opiates nor salicylates, and represent another class of compounds which are useful as analgesic agents.
(2) Description of the Related Art
U.S. Pat. No. 3,357,998 discloses derivatives of dihydrodibenz b,f! 1,4!oxazepine-10-carboxylic acids.
U.S. Pat. No. 5,212,169 discloses a class of substituted dibenzoxazepine compounds in which the 2-, 3- and/or 8-position, and/or the side chain, is substituted.
U.S. Pat. No. 5,182,272 discloses 8-substituted-dibenz b,f! 1,4!oxazepine-10(11)-carboxylic acid, substituted hydrazides, pharmaceutical compositions and methods for treating pain.
U.S. Pat. No. 4,681,939 discloses 8-chlorodibenz b,f! 1,4!oxazepine-10-(11H)-carboxylic acid, 2- (phenylthio)alkanoyl!hydrazides.
U.S. Pat. No. 4,704,386 discloses 8-chlorodibenz b,f! 1,4!oxazepine-10(11)-carboxylic acid, 2- (phenylsulfinyl and phenylsulfonyl)alkanoylhydrazides.
U.S. Pat. No. 3,644,346 discloses semicarbazones of dibenzoxazepine-N-carboxylic acid hydrazides.
U.S. Pat. No. 4,170,593 discloses 1-(substituted amino)alkanoyl-2-(dibenzoxazepine-10-carbonyl) hydrazines and derivatives thereof.
U.S. Pat. Nos. 4,559,336 and 4,614,617 (a continuation-in-part of U.S. Pat. No. 4,559,336) disclose 8-chlorodibenz b,f! 1,4!oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides, and intermediates thereof.
U.S. Pat. No. 3,534,019 discloses hydrazides of dibenzoxazepine-, dibenzothiazepine- and dibenzodiazepine-carboxylic acids.
U.S. Pat. No. 3,624,104 discloses aralkanoyl derivatives of dibenzoxazepine-N-carboxylic acid hydrazide compounds.
U.S. Pat. No. 3,989,719 discloses N,N'-diacyl hydrazines.
U.S. Pat. Nos. 3,917,649 and 3,992,375 (a divisional of U.S. Pat. No. 3,917,649) disclose dibenzoxazepine N-carboxylic acid hydrazine compounds.
U.S. Pat. Nos. 4,045,442, 4,125,532 (a divisional of U.S. Pat. No. 4,045,442) and 4,170,593 (a divisional of U.S. Pat. No. 4,125,532) disclose 1-(substituted amino)alkanoyl-2-(dibenzoxazepine-10-carbonyl)hydrazine compounds.
PCT/US92/03028 discloses a class of substituted dibenzoxazepine compounds in which the 2-, 5- and/or 8-position, and/or the side chain, is substituted.
GB 1 522 003 discloses 1-acyl-2-(8-chloro-10,11-dihydrodibenz b,f! 1,4!oxazepine-10-carbonyl)hydr azine compounds.
GB 1 331 892 discloses derivatives of dibenzoxazepine N-carboxylic acid hydrazides.
W. E. Coyne et al., "Anticonvulsant Semicarbazides," J Med Chem., 11(6), 1158-1160 (1968), disclose the investigation of the structure-activity relationship of the anticonvulsant activity of a series of semicarbazides which was synthesized from various tricyclic amines (see Table I, Page 1160).
Each of the documents described hereinabove discloses compounds which are structurally different from the compounds of the present invention. Thus, the compounds of the present invention are structurally distinct from that which has been described in the art.
Compounds of the present invention have been found to exhibit activity as prostaglandin E.sub.2 antagonists.